Summary
Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B‐cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest ...raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late (i.e., a second lymphoma occurrence occurring after a long period of complete remission). All composite cases were alive in complete remission after a median follow‐up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey‐zone lymphoma.
Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare ...phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
The orphan receptors COUP-TF (chicken ovalbumin upstream promoter transcription factor) I and II are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate ...organogenesis. The involvement of COUP-TFs in cancer development has recently been suggested by several studies but remains poorly understood.
MCF-7 breast cancer cells overexpressing COUP-TFI and human breast tumors were used to investigate the role of COUP-TFI in the regulation of CXCL12/CXCR4 signaling axis in relation to cell growth and migration. We used Immunofluorescence, western-blot, RT-PCR, Formaldehyde-assisted Isolation of Regulatory Elements (FAIRE) assays, as well as cell proliferation and migration assays.
Previously, we showed that COUP-TFI expression is enhanced in breast cancer compared to normal tissue. Here, we report that the CXCL12/CXCR4 signaling pathway, a crucial pathway in cell growth and migration, is an endogenous target of COUP-TFI in breast cancer cells. The overexpression of COUP-TFI in MCF-7 cells inhibits the expression of the chemokine CXCL12 and markedly enhances the expression of its receptor, CXCR4. Our results demonstrate that the modification of CXCL12/CXCR4 expression by COUP-TFI is mediated by the activation of epithelial growth factor (EGF) and the EGF receptor. Furthermore, we provide evidence that these effects of COUP-TFI increase the growth and motility of MCF-7 cells in response to CXCL12. Cell migration toward a CXCL12 gradient was inhibited by AMD3100, a specific antagonist of CXCR4, or in the presence of excess CXCL12 in the cell culture medium. The expression profiles of CXCR4, CXCR7, CXCL12, and COUP-TFI mRNA in 82 breast tumors and control non-tumor samples were measured using real-time PCR. CXCR4 expression was found to be significantly increased in the tumors and correlated with the tumor grade, whereas the expression of CXCL12 was significantly decreased in the tumors compared with the healthy samples. Significantly higher COUP-TFI mRNA expression was also detected in grade 1 tumors.
Together, our mechanistic in vitro assays and in vivo results suggest that a reduction in chemokine CXCL12 expression, with an enhancement of CXCR4 expression, provoked by COUP-TFI, could be associated with an increase in the invasive potential of breast cancer cells.
The use of novel methods to characterize living tumor cells relies on well-conceived biobanks. Herein, we raised the question of whether the composition of fresh and freeze/thawed dissociated tumor ...samples is comparable in terms of quantitative and qualitative profiling.
Breast cancer is a heterogeneous disease, encompassing luminal A and B, basal/triple-negative breast cancer (TNBC), and ERBB2-like tumors. We examined living cells dissociated from TNBC and found that a classical freeze/thaw protocol leads to a marked reduction in the number of CD45
CD44
CD24
tumor cells. This, in turn, changed the percentage of tumor cells with certain CD44/CD24 expression patterns and changed the percentage of tumor-infiltrating immune cells. These cryopreservation-driven alterations in cellular phenotype make it impossible to compare fresh and frozen samples from the same patient directly. Moreover, the freeze/thaw process changed the transcriptomic signatures of triple-negative cancer stem cells in such a manner that hierarchical clustering no longer ranked them according to expected inter-individual differences. Overall, this study suggests that all analyses of living tumor cells should be conducted only using freshly dissociated tumors if we are to generate a robust scoring system for prognostic/predictive markers.
The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain ...incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor–initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.
One-step nucleic acid amplification (OSNA, Sysmex, Kobe, Japan) offers an excellent opportunity for accurate exhaustive sentinel lymph node (SLN) examination in breast cancer patients. Calibrated ...with conventional postoperative histology, this molecular technique yields comparable results intraoperatively, expressed as micrometastasis, macrometastasis or no metastasis depending on the CK19 mRNA copy number amplified in SLN lysates. We applied OSNA to detect metastasis in 810 SLNs from 367 patients with early stage breast cancer. We compared the rate of OSNA-positive SLNs in patients with invasive breast cancer (< 2 cm) versus the rate observed in a historical cohort using conventional histological examination of SLNs. No significant difference was observed, the OSNA assay was positive in 24.4% of patients, compared with positive histology in 24.8% in the historical cohort if including patients with isolated tumour cell (ITC) and in 23.4% excluding them. Opportunities for optimised patient management using OSNA are discussed: intraoperative detection of OSNA-positive SLNs enables axillary lymph node dissection (ALND) during the same procedure; standard OSNA techniques enable the establishment of homogeneous groups based on examination of whole SLNs for valid comparisons between different centres.
ObjectivePeritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic ...difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process.DesignWe performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes.ResultsAbdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAFV600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease.ConclusionDiagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool.
Abstract Aims Achieving negative margins is essential in conservative treatment for breast cancer. The conventional method for intra-operative assessment of resection margins is gross or histological ...examination of frozen sections. We describe and evaluate the contribution of an original intra-operative touch preparation cytology (IOTPC) technique (400 procedures) performed on 396 patients. Materials and methods IOTPC consists of touching glass slides to the surfaces of interest after gently pressing the spatially localized specimen taken according to predetermined conditions. The result is conveyed to the surgeon immediately and compared with the conventional histological findings after embedding in paraffin. Results The average response time is 10 min, which renders the technique compatible with standard operating room procedures and its cost is reasonable. The method has a sensitivity of 88.6%, specificity of 92.2%, positive predictive value of 73.6%, negative predictive value of 97%, and correlation with paraffin section histology of 91.5%. Only 5 true false negatives were found in this series and the technique prevented 11.75% of secondary re-excision procedures for positive margins. Conclusion IOTPC is a reliable extemporaneous method for assessing surgical margins in conservative treatment for breast cancer and a useful tool for surgeons.
There are a large number of gynaecological cancers with rare histologies, for which the available data are limited and usually retrospective. Because of their rarity and poor prognosis, the ...management of these cancers must be centralized in expert centres, for both histological diagnosis and treatment. With the exception of sarcomas, most endometrial or cervical cancers with rare histologies respond to the same radiation treatment modalities than cancers with more common histologies, although there are some specificities regarding treatments such as neuroendocrine carcinomas (chemotherapy with platinum and etoposide, major role of surgery). For localized or locally advanced ovarian cancer, external beam radiotherapy has a role in the management of hypercalcaemic small cell carcinoma of the ovary. This article summarizes the current role of external beam radiotherapy and brachytherapy in the management of cancers of the uterine cervix, uterine corpus and ovaries, with rare or very rare histologies, and with localized or locally advanced stages.
Follicular helper T-cell lymphomas (TFHL) have an aggressive course with a poor outcome. European and US guidelines recommend anthracycline-based chemotherapy as a first-line treatment, but the ...5-year overall survival rate is still approximately 30%. We describe here the features of a cohort of TFHL patients who experienced prolonged survival despite the absence of specific treatment or the initiation of steroid-based therapy.
In our study, we describe 15 adult patients who suffered from TFHL and had not received intensive chemotherapy at diagnosis for any reason. Biopsies of these cases were centrally reviewed, and the mutational pattern was determined using next-generation sequencing.
These 15 patients had the classic clinical, biological and pathological features of TFHL, angioimmunoblastic-type. TET2 mutations were found in 83% of patients; RHOA G17V, IDH2 R172 and DNMT3A mutations were found in 67%, 42% and 33% of the patients, respectively. Among the 15 patients, 8 did not receive any treatment, and 7 received steroid-based treatment. Ten patients had progression (5 in each group). Four patients died (3 of them from the progression of their lymphoma). The median follow-up in our cohort was 53 months. The 5-year OS was 66%, 100% for untreated patients and 29% for the others. In those 2 groups, the median time to treatment initiation was 22 months from diagnosis.
We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted.
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